Immune checkpoint inhibition therapy has emerged as an effective treatment option for various cancer types. However, there are still challenges that need to be addressed. At CCII, research is centered around developing combination therapies that minimize side effects and optimize anti-tumor efficacy. Furthermore, our dedication is oriented towards pushing the boundaries of cancer immunotherapy by advancing novel concepts and approaches. To achieve this, the promotion of both basic and clinical research in the field of cancer immunotherapy is necessary. Moreover, our research endeavors aim to unravel the fundamental principles underlying complex biological phenomena through the study of cancer immunotherapy.
(1) Improving the Outcome of Cancer Immunotherapy
As approved therapeutic applications of anti-PD-1/PD-L1 antibodies, anti-CTLA-4 antibodies, and CAR-T cell therapy have been increasing in recent years in Japan and many other countries, immunotherapy has become established as one of the standard therapies for treating cancer. These novel therapies have shown therapeutic effects with improved prognosis in many cases that could not be treated with conventional therapies.
Currently, efforts are underway to enhance the therapeutic effect of cancer treatment by implementing combination therapies with existing cancer therapies such as chemotherapy, molecular targeted therapy, and radiotherapy. However, it remains a fundamental challenge that more than half of the cases treated do not respond to immune therapies. The reasons behind the unresponsiveness to PD-1 antibody therapy, in particular, are still largely unknown, and gaining a deeper understanding of the mechanisms of action of PD-1 antibodies may lead to improved therapeutic efficacy.
It has become evident that the immune response to cancer is intricately regulated not only by the characteristics of the cancer itself but also by the patient’s lifestyle habits and genetic background. Thus, a comprehensive exploration of non-responsiveness requires research from multiple perspectives and employing a diverse range of methodologies. At CCII, multidisciplinary research is conducted using state-of-the-art technologies such as genomics, proteomics, and metabolomics, utilizing animal models and patient samples.
Building on the findings of CCII’s basic research, several novel combination therapies have been developed and are currently undergoing clinical trials. These trials are conducted in collaboration with the Kyoto University Hospital and the Institute for Advanced Clinical Research and Development (iACT), a clinical research support organization —where the Kyoto Innovation Center for Next-Generation Clinical Trials and iPS Cell Therapy (K-CONNECT), the Clinical Bio-Resource Centre (CBRC), the Department of Clinical Research Facilitation are located—, which is specialized in early-stage clinical trials.
(2) Research on biomarkers
When cancer immunotherapy proves effective, it has often long-lasting effects, whereas in cases where it fails to show any positive response, administering additional doses does not lead to favorable outcomes. Given the escalating healthcare costs, it is crucial to develop biomarkers that can differentiate between patients who respond positively to PD-1 antibody treatment and those who do not.
Therefore, we are conducting research using both clinical samples and mouse models to uncover the underlying mechanisms behind response and non-response to PD-1 inhibition. Additionally, our aim is to identify biomarkers that can accurately predict the therapeutic response to PD-1 antibodies. In collaboration with the Clinical Bio-Resource Center at Kyoto University Hospital, CCII actively collects samples from patients who have undergone immune checkpoint inhibitor therapies.
Since the immune system is closely intertwined with various diseases, including viral infections, autoimmune conditions, and the aging process, our investigations are expected to contribute not only to cancer immunotherapy but also to advancements in other research fields.
(3) Adverse Immunological Events: Linking Clinical Investigation and Basic Research
Immune-related Adverse Events (irAE) are a well-known complication in cancer immunotherapy and can range from simple symptoms such as skin rashes to live-threatening events, such as autoimmune myocarditis. Also, irAE provide a view on the sheer spectrum of immune reactions towards treatment with checkpoint inhibitors and, thus, provide for a strategy to identify human disease “model systems” to study the fundamental biology behind cancer immunotherapy. One strategy we are pursuing at CCII is to build a biobank with tissue samples and clinical data from cancer patients who have experienced Immune-related Adverse Events (irAE) to treatment. A better understanding of the immunobiology behind specific irAEs will eventually lead to better approaches to deal with these events, while providing much needed input data and, in some cases, interesting human model systems. This work is done by CCII in cooperation with Kyoto University Hospital and the Institute for Advanced Clinical Research and Development (iACT), which mainly conducts early-stage clinical trials.